WARNINGS
Application of EMLA Cream to larger areas or for longer times
than those recommended could result in sufficient absorption of
lidocaine and prilocaine resulting in serious adverse effects (see
Individualization of Dose
).
Patients treated with class III anti-arrhythmic drugs (et,
amiodarone, bretylium, sotalol, dofetilide) should be under close
surveillance and ECG monitoring considered, because cardiac effects may
be additive.
Studies in laboratory animals (guinea pigs) have shown that EMLA
Cream has an ototoxic effect when instilled into the middle ear. In
these same studies, animals exposed to EMLA Cream only in the external
auditory canal, showed no abnormality. EMLA Cream should not be used in
any clinical situation when its penetration or migration beyond the
tympanic membrane into the middle ear is possible.
Methemoglobinemia:
EMLA Cream should not be used in those rare patients with
congenital or idiopathic methemoglobinemia and in infants under
the age of twelve months who are receiving treatment with
methemoglobin-inducing agents.
Very young patients or patients with glucose-6-phosphate
dehydrogenase deficiencies are more susceptible to
methemoglobinemia.
Patients taking drugs associated with drug-induced
methemoglobinemia such as sulfonamides, acetaminophen,
acetanilid, aniline dyes, benzocaine, chloroquine, dapsone,
naphthalene, nitrates and nitrites, nitrofurantoin,
nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic
acid, phenacetin, phenobarbital, phenytoin, primaquine, quinine,
are also at greater risk for developing methemoglobinemia.
There have been reports of significant methemoglobinemia
(20 to 30%) in infants and children following excessive
applications of EMLA Cream. These cases involved the use of
large doses, larger than recommended areas of application, or
infants under the age of 3 months who did not have fully mature
enzyme systems. In addition, a few of these cases involved the
concomitant administration of methemoglobin-inducing agents.
Most patients recovered spontaneously after removal of the
cream. Treatment with IV methylene blue may be effective if
required.
Physicians are cautioned to make sure that parents or
other caregivers understand the need for careful application of
EMLA Cream, to ensure that the doses and areas of application
recommended in Table 2 are not exceeded (especially in children
under the age of 3 months) and to limit the period of
application to the minimum required to achieve the desired
anesthesia.
Neonates and infants up to 3 months of age should be
monitored for Met-Hb levels before, during, and after the
application of EMLA Cream, provided the test results can be
obtained quickly.
PRECAUTIONS
General:
Repeated doses of EMLA Cream may increase blood levels of
lidocaine and prilocaine. EMLA Cream should be used
with caution in patients who may be more sensitive to the
systemic effects of lidocaine and prilocaine including acutely
ill, debilitated, or elderly patients.
EMLA cream should not be applied to open wounds.
Care should be taken not to allow EMLA cream to come in
contact with the eye because animal studies have demonstrated
severe eye irritation. Also the loss of protective
reflexes can permit corneal irritation and potential abrasion.
Absorption of EMLA Cream in conjunctival tissues has
not been determined. If eye contact occurs,
immediately wash out the eye with water or saline and protect
the eye until sensation returns.
Patients allergic to paraaminobenzoic acid derivatives
(procaine, tetracaine, benzocaine, etc.) have not shown cross
sensitivity to lidocaine and/or prilocaine, however, EMLA Cream
should be used with caution in patients with a history of drug
sensitivities, especially if the etiologic agent is uncertain.
Patients with severe hepatic disease, because of their
inability to metabolize local anesthetics normally, are at
greater risk of developing toxic plasma concentrations of
lidocaine and prilocaine.
Lidocaine and prilocaine have been shown to inhibit viral
and bacterial growth. The effect of EMLA Cream on
intradermal
injections of
live
vaccines has not been determined.
Information for Patients:
When EMLA Cream is used, the patient should be aware that
the production of dermal analgesia may be accompanied by the
block of all sensations in the treated skin. For this
reason, the patient should avoid inadvertent trauma to the
treated area by scratching, rubbing, or exposure to extreme hot
or cold temperatures until complete sensation has returned.
EMLA cream should not be applied near the eyes or on open
wounds.
Drug Interactions:
EMLA Cream should be used with caution in patients
receiving Class I antiarrhythmic drugs (such as tocainide and
mexiletine) since the toxic effects are additive and potentially
synergistic.
Prilocaine may contribute to
the formation of methemoglobin in patients treated with
other drugs known to cause this condition
(see
Methemoglobinemia
subsection of
WARNINGS
).
Specific interaction studies with lidocaine/prilocaine
and class III anti-arrhythmic drugs (eg, amiodarone, bretylium,
sotalol, doetilide) have not been performed, but caution is
advised (see
WARNINGS
).
Should EMLA Cream be used concomitantly with other
products containing lidocaine and/or prilocaine, cumulative
doses from all formulations must be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis:
Long-term studies in animals designed to evaluate the
carcinogenic potential of lidocaine and prilocaine have not been
conducted.
Metabolites of prilocaine have been shown to be
carcinogenic in laboratory animals. In the animal
studies reported below, doses or blood levels are compared with
the Single Dermal Administration (SDA) of 60 g of EMLA Cream to
400 cm2 for 3 hours to a small person (50 kg).
The typical application of EMLA Cream for one or two
treatments for venipuncture sites (2.5 or 5 g) would be 1/24 or
1/12 of that dose in an adult or about the same mg/kg dose in an
infant.
Chronic oral toxicity studies of
ortho-
toluidine, a metabolite of prilocaine, in mice (450 to
7200 mg/m2; 60 to 960 times SDA) and rats (900 to
4,800 mg/m2; 60 to 320 times SDA) have shown that
ortho-
toluidine is a carcinogen in both species.
The tumors included hepatocarcinomas/adenomas in
female mice, multiple occurrences of
hemangiosarcomas/hemangiomas in both sexes of mice, sarcomas of
multiple organs, transitional-cell carcinomas/papillomas of
urinary bladder in both sexes of rats, subcutaneous
fibromas/fibrosarcomas and mesotheliomas in male rats, and
mammary gland fibroadenomas/adenomas in female rats.
The lowest dose tested (450 mg/m2 in mice,
900 mg/m2 in rats; 60 times SDA) was carcinogenic in
both species. Thus the no-effect dose must be less
than 60 times SDA. The animal studies were conducted
at 150 to 2,400 mg/kg in mice and at 150 to 800 mg/kg in rats.
The dosages have been converted to mg/m2
for the SDA calculations above.
Mutagenesis:
The mutagenic potential of lidocaine HCl has been
tested in a bacterial reverse (Ames) assay in Salmonella, an in
vitro chromosomal aberration assay using human lymphocytes an in
vivo micronucleus test in mice
.
There was no indication of mutagenicity or structural
damage to chromosomes in these tests.
Ortho-
toluidine, a metabolite of prilocaine, at a
concentration of 0.5 μg/mL, was genotoxic in
Escherichia coli
DNA repair and phage-induction assays. Urine
concentrates from rats treated with
ortho-
toluidine (300 mg/kg orally; 300 times SDA) were
mutagenic when examined in
Salmonella typhimurium
in the presence of metabolic activation.
Several other tests on
ortho-
toluidine, including reverse mutations in five
different
Salmonella typhimurium
strains in the presence or absence of metabolic
activation and a study to detect single strand breaks in DNA of
V79 Chinese hamster cells, were negative.
Impairment of Fertility:
See
Use in
Pregnancy
.
Use in Pregnancy: Teratogenic Effects: Pregnancy Category B.
Reproduction studies with lidocaine have been performed
in rats and have revealed no evidence of harm to the fetus (30
mg/kg subcutaneously; 22 times SDA). Reproduction
studies with prilocaine have been performed in rats and have
revealed no evidence of impaired fertility or harm to the fetus
(300 mg/kg intramuscularly; 188 times SDA). There are,
however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not
always predictive of human response, EMLA Cream should be used
during pregnancy only if clearly needed.
Reproduction studies have been performed in rats
receiving subcutaneous administration of an aqueous mixture
containing lidocaine HCl and prilocaine HCl at 1:1 (w/w).
At 40 mg/kg each, a dose equivalent to 29 times SDA
lidocaine and 25 times SDA prilocaine, no teratogenic,
embryotoxic or fetotoxic effects were observed.
Labor and Delivery:
Neither lidocaine nor prilocaine are contraindicated in
labor and delivery. Should EMLA Cream be used
concomitantly with other products containing lidocaine and/or
prilocaine, cumulative doses from all formulations must be
considered.
Nursing Mothers:
Lidocaine, and probably prilocaine, are excreted in human
milk. Therefore, caution should be exercised when EMLA
Cream is administered to a nursing mother since the milk:plasma
ratio of lidocaine is 0.4 and is not determined for
prilocaine.
Pediatric Use:
Controlled studies of EMLA Cream in children under the
age of seven years have shown less overall benefit than in older
children or adults. These results illustrate the
importance of emotional and psychological support of younger
children undergoing medical or surgical procedures.
EMLA Cream should be used with care in patients with
conditions or therapy associated with methemoglobinemia
(see
Methemoglobinemia
subsection of
WARNINGS
).
When using EMLA Cream in young children, especially
infants under the age of 3 months, care must be taken to insure
that the caregiver understands the need to limit the dose and
area of application, and to prevent accidental ingestion (see
DOSAGE AND
ADMINISTRATION
and
Methemoglobinemia
).
In neonates (minimum gestation
age: 37 weeks) and children weighing less than 20 kg,
the area and duration of application should be limited
(see
TABLE 2
in
Individualization of Dose
).
Studies have not demonstrated the efficacy of EMLA Cream
for heel lancing in neonates.
Geriatric Use:
Of the total number of patients in clinical studies of
EMLA Cream, 180 were age 65 to 74 and 138 were 75 and over.
No overall differences in safety or efficacy were
observed between these patients and younger patients.
Other reported clinical experience has not identified
differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals
cannot be ruled out.
Plasma levels of lidocaine and prilocaine in geriatric
and non-geriatric patients following application of a thick
layer of EMLA Cream are very low and well below potentially
toxic levels. However, there are no sufficient data to
evaluate quantitative differences in systemic plasma levels of
lidocaine and prilocaine between geriatric and non-geriatric
patients following application of EMLA Cream.
Consideration should be given for those elderly patients
who have enhanced sensitivity to systemic absorption (see
PRECAUTIONS
).
After intravenous dosing, the elimination half-life of
lidocaine is significantly longer in elderly patients (2.5
hours) than in younger patients (1.5 hours). (See
CLINICAL PHARMACOLOGY
).
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